We study the transmissible spongiform encephalopathies (TSEs or prion disease), which are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). Our goal is to gain a better understanding of the underlying mechansims of TSE diseases in order to develop effective treatments. A key focus of these efforts is to understand the conversion of normal PrP (PrP-sen) to PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. A number of different cell biological, biochemical, biophysical and in vivo experimental approaches have been employed. [unreadable] [unreadable] During FY2006 we have 1) compared the protease-sensitivity and ultrastructures of infectious prion protein particles of different sizes, 2) characterized the mechanism of action of phosphorothioate oligonucleotides and cyclic tetrapyrroles as potent PrP-res inhibitors and anti-TSE drugs in vitro and in vivo, 3) developed a model for a common mechanism of action of anti-TSE compounds, 4) continued to characterize the first tissue culture cell line infected with CWD and identified the first inhibitors of CWD replication, 4) continued to test porphyrins and other inhibitors for prophylactic and therapeutic activities against scrapie in animals , 5) further established the efficacy of a porphyrin against an established central nervous system infection, 6) showed enhanced efficacy of combined treatments with pentosan polysulfate and a porphyrin 7) continued to characterize the adaptation of chronic wasting disease from deer and elk to hamsters and transgenic mice expressing hamster PrP-sen 7) analyzed the prion strain-dependent effects of PrP mutations on PrP conversion to PrP-res 8) developed an in vitro amplification reaction for full-length recombinant PrP and 9) purified and analyzed the ultrastructure of the amyloid plaques from scrapie-infected GPI anchorless PrP transgenic mice.